Published on Web 09/28/2007
Au(I)-Catalyzed Enantioselective 1,3-Dipolar Cycloadditions of Mu2 nchnones with Electron-Deficient Alkenes Asa D. Melhado, Marco Luparia, and F. Dean Toste* Department of Chemistry, UniVersity of California, Berkeley, California 94720 Received July 17, 2007; E-mail:
[email protected] Synthetic methods relying on gold complexes as catalysts have recently been the focus of intense development.1 Despite numerous advances, relatively few enantioselective gold-catalyzed transformations have been described. The earliest example of an enantioselective gold(I)-catalyzed transformation, the Hayashi-Ito aldol reaction, was proposed to rely on activation of the nucleophile as a chiral monophosphineAu(I) enolate.2 In contrast, the majority of recently reported methods rely on the electrophilic nature of cationic bisphosphinegold(I) complexes to activate π-bonds toward addition of nucleophiles.3 Therefore, the utility of chiral bisphosphinegold(I) complexes would be signficantly extended if they could be employed as catalysts for enantioselective transformations that are not predicated on π-bond activation. To this end, herein we describe the development of a bisphosphinegold(I)-catalyzed enantioselective 1,3-dipolar cycloaddition4 reaction of mesoionic azomethine ylides (mu¨nchnones) with alkenes. We were inspired by Tepe’s recent report of silver(I)acetatecatalyzed mu¨nchnone/alkene 1,3-dipolar cycloadditions,5,6 to consider the use of our recently developed bisphosphinegold(I) carboxylate complexes as catalysts for this transformation.3c Gratifyingly, treatment of a THF solution of azlactone 1a and 1.5 equiv of N-phenylmaleimide (3) with 2 mol % triphenylphosphinegold(I) benzoate at room temperature, followed by in situ esterification, afforded the desired ∆1-pyrroline (()-2a in 85% yield with excellent diastereoselectivity (Table 1, entry 1). Having established an achiral phosphinegold(I) benzoate as a catalyst for the formation for 2a, we next focused on the enantioselective reaction of 1a and 3 (Table 1). In general, the diphenyl-substituted biarylphosphinegold(I) benzoate complexes successfully employed in the hydroamination gave modest selectivity for the reaction of 1a and 3 (entries 2-5). While substitution on the phosphine aryl ring resulted in improved selectivity (entry 8), we were pleased to find the (S)-Cy-SEGPHOS(AuOBz)2 (4)7-catalyzed cycloaddition gave 2a with a notable increase in enantioselectivity (88% ee) (entry 9). Further optimization of reaction conditions revealed that the reaction performed similarly in various solvents;8 however, employing fluorobenzene (PhF) as the solvent produced a further improvement and provided 2a in 76% yield and 95% ee (entry 10).9 Notably, in all cases only the exo-adduct was observed.
A variety of electron-deficient alkenes were found to be viable dipolarophiles in the gold(I)-catalyzed mu¨nchnone cycloaddition. For example, 2 mol % gold(I) benzoate 4-catalyzed the reaction of 1a with maleic anhydride (5), under conditions similar to those used with N-phenylmaleimide to afford acid 6 in 79% yield and 12638
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Table 1. Development of the Au(I)-Catalyzed Cycloadditiona
entry
catalyst
time (h)
yield (%)b
ee (%)c
1 2 3 4 5 6 7 8 9 10
PPh3AuOBz (R)-BINAP(AuOBz)2 (R)-SEGPHOS(AuOBz)2 (R)-DIFLUOROPHOS(AuOBz)2 (R)-Cl-MeO-BiPHEP(AuOBz)2 (R)-SYNPHOS(AuOBz)2 (R)-3,5-xylyl-BINAP(AuOBz)2 (R)-DTBM-SEGPHOS(AuOBz)2 (S)-Cy-SEGPHOS(AuOBz)2, (4) 4
0.5 2 3 3 3 3 3 7 2 5
85 78 81 56 80 62 63 81 70 76
-8 -40 -44 -5 -55 -24 -83 88 95d
a Reactions run with 0.33 mmol 1a; for conditions concerning in situ ester formation see Supporting Information (SI). b Isolated yield. c Absolute configuration determined by X-ray crystallography on the corresponding R-methylbenzylamide (see SI). d Reaction performed at 0.5 M in PhF.
Table 2. Reaction of 1a with Various Acyclic Alkenesa
entry
1 2 3 4 5
product
7a, X ) CO2 7b, X ) CO2tBu 7c, X ) CO2Et 7d, X ) CO2Me 7e, X ) CN tBu
R ) OMe R ) NHCH2Ph R ) OMe R ) OMe R ) NHCH2Ph
time (h)
yield (%)b
ee (%)
24 14 14 14 14
56 74 66 89d 68
99c 95 90 93 76
a Reactions run with 0.33 mmol 1a at 0.5 M; for conditions concerning in situ ester/amide formation see SI. b Isolated yield unless otherwise noted. c Reaction run with 10 equiv of alkene and 2% mol 4. d Yield determined by 1H NMR.
87% ee (eq 1).10 Acyclic alkenes could also be employed as partners in the gold(I)-catalyzed cycloaddition (Table 2). Generally, the reactions performed best using a 3:1 mixture of THF and PhF and slightly higher catalyst loading (3.5%). Notably, in all cases the reactions proceeded with excellent diastereo- and regioselectivity. Various azlactones (1b-j) were prepared, and the results of their gold(I) benzoate-catalyzed enantioselective cycloaddition with N-phenylmaleimide are shown in Table 3. Substitution at the para position of the azlactone aromatic ring was well tolerated (entries 1-4). While increasing the steric demand at the azlactone C2 or C4 position resulted in decreased reactivity in PhF, switching the solvent to a mixture of THF and PhF permitted isolation of the cycloadducts in good yields (entries 5, and 7-9). The use of this solvent mixture allowed for smooth reaction of azlactone 1f, bearing 10.1021/ja074824t CCC: $37.00 © 2007 American Chemical Society
COMMUNICATIONS Table 3. Reaction of N-Phenylmaleimide (3) with Azlactonesa
entry
1 2 3 4 5 6 7 8 9
product
b, R ) Me c, R ) Me d, R ) Me e, R ) Me f, R ) Me g, R ) H h, R ) allyl i, R ) Ph j, R ) Bn
Ar ) p-MeO-C6H4Ar ) p-Br-C6H4Ar ) p-Cl-C6H4Ar ) p-NO2C6H4Ar ) o-Me-C6H4Ar ) Ph Ar ) Ph Ar ) Ph Ar ) Ph
time (h)
yield (%)b
ee (%)
18 15 15 1.5 4 24 8 1.5 36
77 75 72 98 73 84 86 35 71
95 93 92 91 86c -98d 87c 78e 68c
a Reactions run with 0.33 mmol azlactone; for conditions concerning in situ ester formation see SI. b Isolated yield. c Run at 0.5 M in 3:1 THF/ PhF. d At 0.5 M in aceteone, using (R)-DTBM-SEGPHOS(AuOBz)2; note also the change in the sense of ligand chirality. e Run at 0.25 M in 3:1 THF/PhF at 0 °C with 5% mol 4.
Scheme 1. Proposed Mechanism of Au(I)-Catalyzed 1,3-DCR
a 2-methylphenyl C2 substituent, providing product 2f in good yield with 86% ee.11 Similarly, C4 allyl-substituted azlactone 1h underwent gold(I)-catalyzed cycloaddition to furnish 2h in 86% yield and 87% ee; however, a decrease in enantioselectivity was observed with a further increase in the size of the C4 substituent to benzyl (entry 9). The reaction of 3 with glycine-derived azlactone 1g catalyzed by 4 produced 2g with only 81% ee. Fortunately, switching the catalyst to (R)-DTBM-SEGPHOS(AuOBz)2 allowed for the isolation of cycloadduct 2g in 84% yield and 98% ee (entry 6). A proposed catalytic mechanism, paralleling those postulated for reactions of acyclic azomethine ylides, is shown in Scheme 1.6 Dissociation of a carboxylate counterion from 8 provides an open coordination site for azlactone binding. Deprotonation of the activated substrate, presumably by benzoate, generates N-aurateddipole 9. Reaction of 9 with the dipolarophile produces initial cycloadduct 10. Subsequent C-O bond cleavage and protonation followed by dissociation of the ∆1-pyrroline regenerates the catalyst.12 In summary, we have developed the first catalytic enantioselective reaction of azlactones with alkenes to provide ∆1-pyrrolines.13,14 Notably, the gold-catalyzed cycloadditions proceed with excellent diastereo- and regioselectivity. The reaction is proposed to proceed through a 1,3-dipole15 generated by deprotonation of a gold(I)-
activated azlactone and therefore represents an important departure from the mechanistic paradigm of π-activation most commonly proposed in contemporary asymmetric catalysis with gold complexes. The development of enantioselective reactions relying on gold(I)-catalyzed generation of nucleophiles is ongoing and will be reported in due course. Acknowledgment. We gratefully acknowledge NIHGMS (R01 GM073932), Merck Research Laboratories, Bristol-Myers Squibb, Amgen Inc., DuPont, GlaxoSmithKline, Eli Lilly & Co., Pfizer, and AstraZeneca for funding. M.L. thanks Italian MIUR for a graduate fellowship. We thank Takasago International Corporation for their generous donation of SEGPHOS ligands. Supporting Information Available: Experimental procedures and compound characterization data; X-ray crystallgraphic data. This material is available free of charge via the Internet at http://pubs.acs.org. References (1) For recent reviews see: (a) Jime´nez-Nu´n˜ez, E.; Echavarren, A. M. Chem. Commun. 2007, 333. (b) Furstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 2. (c) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395. (2) Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405. (3) (a) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007, 317, 496. (b) Liu, C.; Widenhoefer, R. A. Org. Lett. 2007, 9, 1935. (c) LaLonde, R. L.; Sherry, B. D.; Kang, E. J.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 2452. (d) Zhang, Z.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2007, 46, 283. (e) Johansson, M. J.; Gorin, D. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 18002. (f) Munoz, M. P.; Adrio, J.; Carretero, J. C.; Echavarren, A. M. Organometallics 2005, 24, 1293. (4) For reviews on asymmetric 1,3-dipolar cycloaddition reactions see: (a) Pellissier, H. Tetrahderon 2007, 3235. (b) Kanemassa, S. Synlett 2002, 1371. (c) Gothelf, K. V. Synthesis 2002, 211. (d) Gothelf, K. V.; Jorgensen, K. A. Chem. ReV. 1998, 98, 863. (5) Peddibhotla, S.; Tepe, J. J. Am. Chem. Soc. 2004, 126, 12776. (6) For selected reports of transition-metal-catalyzed asymmetric azomethine ylide cycloadditions see: (a) Saito, S.; Tsubogo, T.; Kobayashi, S. J. Am. Chem. Soc. 2007, 129, 5364. (b) Zeng, W.; Chen, G.-Y.; Zhou, Y.-G.; Li, Y.-X. J. Am. Chem. Soc. 2007, 129, 705. (c) Cabrera, S.; Arrayas, R. G.; Carretero, J. C. J. Am. Chem. Soc. 2005, 127, 16394. (d) Zeng, W.; Zhou, Y.-G. Org. Lett. 2005, 7, 5055. (e) Gao, W.; Zhang, X.; Raghunath, M. Org. Lett. 2005, 7, 4241. (f) Oderaotoshi, Y.; Cheng, W.; Fujimoto, S.; Kasano, Y.; Minkata, S.; Komatsu, M. Org. Lett. 2003, 5, 5043. (g) Chen, C.; Li, X.; Schreiber, S. J. Am. Chem. Soc. 2003, 125, 10174. (h) Longmire, J.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400. For a review see: (i) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. ReV. 2006, 106, 4484. (7) See Supporting Information (SI) for an X-ray structure of (S)-CySEGPHOS(AuCl)2. (8) THF (2 h, 70%, 88% ee), acetone (2 h, 82%, 85% ee), DME (3 h, 79%, 87% ee), CH2Cl2 (5 h, 59%, 88% ee), benzene (5 h, 64%, 88% ee), toluene (5 h, 62%, 87% ee). (9) Under these conditions, the choice of carboxylate counterion had no notable effect on the reaction. (benzoate, 5 h, 76%, 95% ee; pnitrobenzoate, 5 h, 70%, 95% ee; acetate, 5 h, 71%, 95% ee). (10) Cycloadduct 6 was not isolated; yield determined by 1H NMR (see SI). (11) Reaction of 2,4-dimethyl-2-oxazolin-5-one with 3, catalyzed by 4, gave the cycloadduct in 39% ee. (12) Maryanoff, C. A.; Turchi, I. J. Heterocycles 1993, 649. (13) Reaction of 1a and 3 catalyzed by 10% AgOAc, 10% (S)-QUINAP6g afforded 2a in 14% yield and 5% ee after 12 hr at -20 °C in THF. (14) For recent examples of metal-catalyzed processes proceeding through mu¨nchnones, see: (a) Dhawan, R.; Arndtsen, B. J. Am. Chem. Soc. 2004, 126, 468. (b) Dhawan, R.; Dghaym, R. D.; Arndtsen, B. J. Am. Chem. Soc. 2003, 125, 1474. (15) For examples of gold-catalyzed processes proposed to proceed via reaction of a C-aurated 1,3-dipole generated by activation of an alkyne, see: (a) Asao, N.; Aikawa, H. J. Org. Chem. 2006, 71, 5253. (b) Kim, N.; Kim, Y.; Park, W.; Sung, D.; Gupta, A. K.; Oh, C. H. Org. Lett. 2005, 7, 5289. (c) Asao, N.; Sato, K.; Menggenbateer; Yamamoto, Y. J. Org. Chem. 2005, 70, 3682. (d) Asao, N.; Aikawa, H.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 7458. (e) Straub, B. F. Chem. Commun. 2004, 1726. (f) Asao, N.; Nogami, T.; Lee, S.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 10921. (g) Asao, N.; Takahashi, K.; Lee, S.; Kasahara, T.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 12650. For the sole example concerning azomethine ylides, see: (h) Kusama, H.; Miyashita, Y.; Takaya, J.; Iwasawa, N. Org. Lett. 2006, 8, 289.
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